Targeting RAS membrane association
RAS proteins are synthesized as globular hydrophilic proteins that are secondarily targeted to cellular membranes by a series of C-terminal posttranslational modifications. These include prenylation, endoproteolysis, and carboxymethylation of a C-terminal CaaX motif and, for three of the four RAS proteins, subsequent palmitoylation of nearby cysteines. Once it was discovered that oncogenic mutant RAS proteins required membrane association to promote malignancy, the enzymes that catalyze these posttranslational modifications became prime targets for anticancer drug discovery. Farnesyltransferase inhibitors, the most successful agents in this class, failed in the clinic against KRAS-driven tumors because alternative prenylation preserved membrane association. However, the idea of blocking membrane association to inhibit oncogenic RAS remains viable and attractive with new knowledge that direct RAS inhibitors are unlikely to suffice as monotherapy. This chapter reviews the pathways of RAS membrane association and the various approaches taken to interfere with them.
